The antineoplastic activity of podophyllotoxin is well documented. However, since it is extremely toxic, it has rarely been used in treating humans. Accordingly, various derivatives of podophyllotoxin have been developed over the years in an attempt to obtain antineoplastic compounds with reduced toxicity. For instance, etoposide and teniposide have reduced toxicity and have exhibited antineoplastic activity against certain tumors, including small-cell carcinoma of the lung, acute leukemia, malignant lymphoma, and testicular cancer.
In the preparation of various derivatives of podophyllotoxin it has been suggested, as exemplified by U.S. Pat. No. 3,524,844 to Keller-Juslen, et al., to prepare 4-bromo-4'-demethylepipodophyllotoxin by reacting podophyllotoxin with hydrogen bromide. The reaction suggested therein is carried out at -20.degree. C. to +40.degree. C. and preferably at 0.degree. C. and employing solutions of, for example, ethylene chloride saturated with hydrogen bromide gas.
In addition, a number of other derivatives of podophyllotoxin have been suggested as antitumor agents, including those discussed in Australian Application No. 31224/844 Japanese Kokai No. 63-10780; Japanese Kokai 63-23884; Thurston, Synthesis and Biological Evaluation of Antitumor Analogues of Podophyllotoxin and .alpha.-Peltatin, University of North Carolina, 1986; Saito, et al., "Studies of Lignan Lactone Antitumor Agents. I. Synthesis of Aminoglycosidic Lignan Variants Related to Podophyllotoxin", Chem Pharm Bull, 34(9):3733-3740 (1986); and Saito, et al., "Studies in Lignan Lactone Antitumor Agents II Synthesis of N-Alkylamino and 2,6-Dideoxy-2-Aminoglycosidic Lignan Variants Related to Podophyllotoxin", Chem Pharm Bull, 34(9):3741-3746 (1986). Additionally, Japanese Patent Application 1093-589A disclosed in Derwent Abstract No. 89-153953/21 and Lee, et al., J of Natural Products, 52(3):606-6113 (May-June 1989), define derivatives of 4'-demethylepipodophyllotoxin as antitumor agents.
Furthermore, various processes have been suggested for producing certain derivatives of podophyllotoxin such as in U.S. Pat. No. 4,564,675 and European Patent Publications 0162701 and 226202.